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Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response

Nature volume 533, pages 416–419 (2016)Cite this article

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Abstract

Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the deletion genome is enriched, OXPHOS declines, resulting in cellular dysfunction. For example, Kearns–Sayre syndrome is caused by a single heteroplasmic mtDNA deletion. More broadly, mtDNA deletion accumulation has been observed in individual muscle cells1 and dopaminergic neurons2 during ageing. It is unclear how mtDNA deletions are tolerated or how they are propagated in somatic cells. One mechanism by which cells respond to OXPHOS dysfunction is by activating the mitochondrial unfolded protein response (UPRmt), a transcriptional response mediated by the transcription factor ATFS-1 that promotes the recovery and regeneration of defective mitochondria3,4. Here we investigate the role of ATFS-1 in the maintenance and propagation of a deleterious mtDNA in a heteroplasmic Caenorhabditis elegans strain that stably expresses wild-type mtDNA and mtDNA with a 3.1-kilobase deletion (∆mtDNA) lacking four essential genes5. The heteroplasmic strain, which has 60% ∆mtDNA, displays modest mitochondrial dysfunction and constitutive UPRmt activation. ATFS-1 impairment reduced the ∆mtDNA nearly tenfold, decreasing the total percentage to 7%. We propose that in the context of mtDNA heteroplasmy, UPRmt activation caused by OXPHOS defects propagates or maintains the deleterious mtDNA in an attempt to recover OXPHOS activity by promoting mitochondrial biogenesis and dynamics.

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Figure 1: ATFS-1 is required to maintain a deleterious mtDNA.
Figure 2: ATFS-1 promotes ∆mtDNA maintenance and mitochondrial biogenesis largely independent of Parkin.
Figure 3: ATFS-1 activation causes deleterious mtDNA expansion.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in a MIAME-compliant format to the Gene Expression Omnibus database under accession number GSE73669.

References

  1. Bua, E. et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79, 469–480 (2006)

    Article  CAS  Google Scholar 

  2. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518–520 (2006)

    Article  CAS  Google Scholar 

  3. Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P. & Haynes, C. M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol. Cell 58, 123–133 (2015)

    Article  CAS  Google Scholar 

  4. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012)

    Article  ADS  CAS  Google Scholar 

  5. Tsang, W. Y. & Lemire, B. D. Stable heteroplasmy but differential inheritance of a large mitochondrial DNA deletion in nematodes. Biochem. Cell Biol. 80, 645–654 (2002)

    Article  CAS  Google Scholar 

  6. Greaves, L. C. et al. Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. PLoS Genet. 10, e1004620 (2014)

    Article  Google Scholar 

  7. Taylor, S. D. et al. Targeted enrichment and high-resolution digital profiling of mitochondrial DNA deletions in human brain. Aging Cell 13, 29–38 (2014)

    Article  CAS  Google Scholar 

  8. Stewart, J. B. & Chinnery, P. F. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 16, 530–542 (2015)

    Article  CAS  Google Scholar 

  9. Yoneda, T. et al. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J. Cell Sci. 117, 4055–4066 (2004)

    Article  CAS  Google Scholar 

  10. Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011)

    Article  CAS  Google Scholar 

  11. Baker, B. M., Nargund, A. M., Sun, T. & Haynes, C. M. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2. PLoS Genet. 8, e1002760 (2012)

    Article  CAS  Google Scholar 

  12. Haynes, C. M., Petrova, K., Benedetti, C., Yang, Y. & Ron, D. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev. Cell 13, 467–480 (2007)

    Article  CAS  Google Scholar 

  13. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010)

    Article  Google Scholar 

  14. Valenci, I., Yonai, L., Bar-Yaacov, D., Mishmar, D. & Ben-Zvi, A. Parkin modulates heteroplasmy of truncated mtDNA in Caenorhabditis elegans. Mitochondrion 20, 64–70 (2015)

    Article  CAS  Google Scholar 

  15. Suen, D. F., Narendra, D. P., Tanaka, A., Manfredi, G. & Youle, R. J. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc. Natl Acad. Sci. USA 107, 11835–11840 (2010)

    Article  ADS  CAS  Google Scholar 

  16. Scarffe, L. A., Stevens, D. A., Dawson, V. L. & Dawson, T. M. Parkin and PINK1: much more than mitophagy. Trends Neurosci. 37, 315–324 (2014)

    Article  CAS  Google Scholar 

  17. Jin, S. M. & Youle, R. J. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy 9, 1750–1757 (2013)

    Article  CAS  Google Scholar 

  18. Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015)

    Article  ADS  CAS  Google Scholar 

  19. Rauthan, M., Ranji, P., Aguilera Pradenas, N., Pitot, C. & Pilon, M. The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway. Proc. Natl Acad. Sci. USA 110, 5981–5986 (2013)

    Article  ADS  CAS  Google Scholar 

  20. Mishra, P., Carelli, V., Manfredi, G. & Chan, D. C. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 19, 630–641 (2014)

    Article  CAS  Google Scholar 

  21. Chen, H. et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141, 280–289 (2010)

    Article  CAS  Google Scholar 

  22. Nakada, K. et al. Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat. Med. 7, 934–940 (2001)

    Article  CAS  Google Scholar 

  23. Pellegrino, M. W. et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014)

    Article  ADS  CAS  Google Scholar 

  24. Schieber, M. & Chandel, N. S. TOR signaling couples oxygen sensing to lifespan in C. elegans. Cell Reports 9, 9–15 (2014)

    Article  CAS  Google Scholar 

  25. Lamech, L. T. & Haynes, C. M. The unpredictability of prolonged activation of stress response pathways. J. Cell Biol. 209, 781–787 (2015)

    Article  CAS  Google Scholar 

  26. He, L. et al. Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res. 30, e68 (2002)

    Article  Google Scholar 

  27. Bargmann, C. I., Hartwieg, E. & Horvitz, H. R. Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell 74, 515–527 (1993)

    Article  CAS  Google Scholar 

  28. Andreux, P. A. et al. A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans. Sci. Rep. 4, 5285 (2014)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Lemire, the National Bioresource Project and the Caenorhabditis Genetics Center for providing C. elegans strains (funded by NIH Office of Research 362 Infrastructure Programs (P40 OD010440), and the Genomics and Bioinformatics Facilities at Memorial Sloan Kettering Cancer Center). This work was supported by National Institutes of Health grants (R01AG040061 and R01AG047182) to C.M.H. and (R01HD078703 and R01NS081490) to S.S., and a Parkinson’s Disease Foundation grant (PDF-FBS-1314) to Y.-F.L. and Deutsche Forschungsgemeinschaft (DFG, SCHU 3023/1-1) to A.M.S.

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Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Yi-Fan Lin, Anna M. Schulz, Mark W. Pellegrino & Cole M. Haynes

  2. Laboratory of Developmental Genetics, The Rockefeller University, New York, 10065, New York, USA

    Yun Lu & Shai Shaham

  3. BCMB Allied Program, Weill Cornell Medical College, 1300 York Avenue, New York, 10065, New York, USA

    Cole M. Haynes

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  1. Yi-Fan Lin
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Contributions

Y.-F.L. and C.M.H. planned the experiments. Y.-F.L. generated the worm strains and performed the mtDNA quantification and obtained the images. A.M.S. and Y.-F.L. performed the oxygen consumption analysis and M.W.P. performed the microarray experiments. Electron microscopy was performed by Y.Lu under the supervision of S.S. Y.-F.L. and C.M.H. wrote the manuscript.

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Correspondence to Cole M. Haynes.

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Extended data figures and tables

Extended Data Figure 1 RNAi of nuclear encoded OXPHOS components activates the UPRmt, and UPRmt signalling components are required for ∆mtDNA propagation.

a, Images of hsp-6pr::gfp worms raised on nuo-2 (complex I), cyc-1 (cytochrome c) or atp-2 (complex V) RNAi. Scale bar, 0.1 mm. b, Relative ∆mtDNA quantification as determined by qPCR in ∆mtDNA or atfs-1(tm4525);∆mtDNA worms. n = 3; error bars, mean ± s.d.; *P < 0.03 (Student’s t-test). c, Relative ∆mtDNA quantification as determined by qPCR in ∆mtDNA worms raised on control, dve-1, or ubl-5 RNAi. n = 3; error bars, mean ± s.d.; *P < 0.03 (Student’s t-test). d, Images of dve-1pr::dve-1::gfp in wild-type or ∆mtDNA worms. Scale bar, 0.1 mm. e, Ratios of ∆mtDNA and nuclear genomic DNA as determined by qPCR in individual ∆mtDNA and atfs-1(tm4919);∆mtDNA worms. Black bars represent the mean. n = 16; mean P < 0.0001 (Student’s t-test).

Extended Data Figure 2 The reduction in ∆mtDNA caused by atfs-1(RNAi) is largely independent of autophagy, and ATFS-1 activation in the presence of a deleterious mtDNA is harmful.

a, Relative ∆mtDNA quantification as determined by qPCR in ∆mtDNA and atg-18(gk378);∆mtDNA worms raised on control or atfs-1 RNAi. n = 3; error bars, mean ± s.d.; *P < 0.03 (Student’s t-test). b, Images of hsp-6pr::gfp worms raised on control or spg-7 RNAi. Scale bar, 0.1 mm. c, Images of TMRE-stained wild-type, ∆mtDNA, atfs-1(et18) and atfs-1(et18);∆mtDNA worms. Scale bar, 0.1 mm. d, Images of synchronized atfs-1(et18) and atfs-1(et18);∆mtDNA worms raised on 2.5 μM rotenone 4 days after hatching. Scale bar, 1 mm.

Extended Data Figure 3 polg-1, hmg-5 and drp-1 mRNAs are induced in atfs-1(et18) worms, and mitochondrial fusion is required for the development of atfs-1(et18) worms harbouring ∆mtDNA.

a, polg-1, hmg-5 and drp-1 transcripts as determined by qRT–PCR in wild-type and atfs-1(et18) worms. n = 3; error bars, mean ± s.d.; *P < 0.03 (Student’s t-test). RFU, random fluorescent units. b, Images of synchronized ∆mtDNA, atfs-1(et18), and atfs-1(et18);∆mtDNA worms raised on control or fzo-1 RNAi. Scale bar, 1 mm. c, ∆mtDNA quantification as determined by qPCR in ∆mtDNA worms raised on control or hmg-5 RNAi. n = 3; error bars, mean ± s.d.; *P < 0.03 (Student’s t-test).

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Supplementary Tables

This file contains Supplementary Tables 1-2 comprising: (1) the relative fold induction and P values for each mRNA and (2) list of Primers that specifically amplify wild-type or ΔmtDNA . (PDF 242 kb)

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Lin, YF., Schulz, A., Pellegrino, M. et al. Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature 533, 416–419 (2016). https://doi.org/10.1038/nature17989

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